Mixed Connective Tissue Disease Research Articles

Combination of cytoplasmic and nuclear patterns on Hep-2 antinuclear antibody is useful as a screening test for anti-synthetase syndrome.

This study aimed to establish a screening model for differentiating anti-synthetase syndrome (ASS) from other antinuclear antibody (ANA)-associated rheumatic diseases (AARD) using a combination of cytoplasmic and non-cytoplasmic ANA (ncANA) patterns. This retrospective observational study included patients with AARDs such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), and polymyositis/dermatomyositis (PM/DM) who underwent ANA screening between April 2012 and December 2021. Variables included age, sex, ANA patterns (Cytoplasmic and ncANA), and titers. Logistic regression analysis of Cytoplasmic and ncANA patterns was performed to differentiate ASS from other AARDs. The 981 diagnosed cases of AARDs consisted of SS (n = 451), SSc (n = 264), SLE (n = 201), PM/DM (n = 104), MCTD (n = 52), and ASS, including PM/DM (n = 64). Of these, 155 patients had ≥2 overlapping diseases; however, there was no overlap between AARDs and ASS. ASS is more likely to occur when the cytoplasmic titer is positive and the ncANA <320. Receiver operating characteristic (ROC) analysis of the Cytoplasmic and ncANA range revealed an area under the ROC curve (AUC) of 0.885 (95% CI: 0.844 to 0.927). It is important to detect cytoplasmic patterns as an ANA screening test for ASS diagnosis, even if the titer is low. Additionally, combining the cytoplasmic and ncANA patterns yields more accurate ASS screening results.

Heterogeneity of right ventricular echocardiographic parameters in systemic lupus erythematosus among four clinical subgroups, as stratified by clinical organ involvement in observational cohort

BackgroundSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Cardiac involvement in SLE is rare but plays an important prognostic role. The degree of cardiac involvement according to SLE subsets...

Pachydermoperiostosis Mimicking Acromegaly: a Rare Case Report in Sardjito General Hospital Yogyakarta Indonesia

Pachydermoperiostosis is a genetic disorder characterized by pachydermia and periostosis. The clinical and radiological features of pachydermoperiostosis are similar to acromegaly. The Prevalence of pachydermoperiostosis is estimated 0.16%. The ratio of male-to-female incidence is 7 to 1. We report a man 26 years old with complaints of pain and swelling in the wrist joints, fingers, knee joints and ankle joints bilaterally; seborrheic dermatitis, eyelid ptosis, and thickening of facial skin, which has been progressive since he was 17 years old. Manus, genu and pedis x-ray results showed a features of mixed connective tissue disease. Magnetic resonance imaging result of the pituitary gland with contrast was normal. Laboratory results for growth hormone (GH) and insulin growth factor-1 (IGF-1) were normal. Histopathology results of the facial skin biopsy showed grade 1 pachydermia in pachydermoperiostosis. In conclusion, the appearance of pachydermia on skin biopsy, with normal growth hormone and insulin growth factor-1 results can differentiate pachydermoperiostosis from acromegaly.

E064 Identifying patients with pulmonary disease in a mixed connective tissue disease cohort

Abstract Background/Aims Respiratory involvement specifically interstitial lung disease (ILD) is a recognised complication of mixed connective tissue disease (MCTD), with a reported prevalence ranging from 40-78%. Surveillance for ILD in other connective tissue diseases such as systemic sclerosis is established clinical practice. Using guidelines recently published by the American College of Rheumatology (2023) we undertook a service evaluation to evaluate current practice for patients in our centre. Methods Electronic case notes were searched using key terms ‘mixed connective tissue disease’, ‘MCTD’ and ‘anti-RNP positive’ to identify patients seen between January 2021-2023. Patients identified were then compared against three MCTD classification criteria (Sharp et al, Alarcon-Sergovia et al and Kasukawa et al). To ensure a robust diagnosis, only those meeting the classification threshold on two or more criterion were included. Results 56 patients were identified however only 44 met two classification criteria and were subsequently included. Mean age was 47.3 years with 40/44 (91%) female. 28/44 (64%) had previous CT chest imaging. In the remaining 16/44 (46%), none had reported symptoms suggestive of ILD in preceding two years. 34/44 (77%) patients had previous pulmonary function testing. In those without, 1/10 had recently reported dyspnoea. 9/44 (20%) had identified MCTD-ILD of which 7/9 (30%) were on immunosuppression, 3/9 for predominant lung disease. Of those with ILD, 7/9 (78%) had had PFTs in the last year. No patients with ILD had undergone assessment for ambulatory desaturation. 7/9 (78%) patients with ILD had received specialist respiratory input, 1 had been seen in a general respiratory clinic, and in 1 case it was unknown. All patients with identified ILD who met established criteria for treatment were receiving immunosuppression. No patient met criteria for progressive fibrotic ILD. No specific disease characteristics (utilising clinical criterion from classification criteria) were demonstrated to have association with ILD (statistical analysis performed using the chi-squared test). No association was demonstrated in patients displaying anti- Ro52 and Ro60 positivity and ILD. Conclusion This evaluation has highlighted that patients with identified MCTD-ILD are being treated and monitored well. However further surveillance for pulmonary involvement both at baseline and then subsequent interval pulmonary function testing needs to improve. This may account for the lower prevalence of ILD in our MCTD cohort in comparison to the literature. Surveillance of pulmonary involvement should take place regardless of clinical disease manifestations displayed. We need to establish feasibility for ambulatory desaturation testing in those with ILD within our outpatient setting. With increasing immunomodulatory treatment available identifying patients with MCTD-ILD is imperative. Disclosure R. Benson: None. K. Mashida: None. M. Ahmad: None. L.G. Spencer: None. Z. McLaren: None. T. Barnes: None.

OA14 Subcutaneous panniculitis-like T-cell lymphoma: a mimic of lupus erythematous panniculitis

Abstract Background/Aims Lupus erythematosus panniculitis (LEP) is a rare variant of cutaneous lupus erythematosus characterised by tender, erythematous subcutaneous nodules or plaques on the face, trunk and proximal extremities. Without treatment, profound lipoatrophy frequently occurs, which often has a devastating psychosocial impact. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cutaneous T-cell lymphoma, which may appear in a similar manner. SPTCL initially preferentially infiltrates the subcutaneous adipose tissue and symptoms vary widely depending on the stage of the disease. Early-stage disease presents as painless self-resolving subcutaneous nodules on limbs and trunk. Methods We present the case of a young woman who presented with progressively developing, widespread painful cutaneous lesions, pyrexia of unknown origin and general malaise for one month. She had a history of hurthle cell neoplasm and a strong family history of malignancy. Initial examination revealed 1-2 cm firm, skin-coloured subcutaneous nodules over her lower back, chest and thigh, with groin and axillary lymphadenopathy. Further lesions progressively developed over a three-month period, with lesions turning increasingly erythematous and with associated ulceration. Of note, a significant periorbital lesion appeared, associated with an ipsilateral facial palsy. Results Initial bloods revealed an elevated LDH with cholestatic liver function tests. PET-CT imaging showed an enlarged axillary node with extensive pathology throughout the subcutaneous fat of unknown aetiology. Due to the family history, underlying haematological malignancy and atypical Sweet’s were considered for this unusual presentation. Seropositivity for anti-Ro and ENA, alongside raised angiotensin converting enzyme, broadened the differentials to include LEP, mixed atypical connective tissue disease and cutaneous sarcoid. Notably, complement, myositis panel and creatine kinase were normal. Lupus vulgaris was considered due to high local prevalence and excluded with T-SPOT testing. Histopathological analysis of lesional skin from the upper arm found predominantly subcutaneous infiltrates of atypical lymphoid cells with irregular hyperchromatic nuclei and rimming of individual fat cells. T-cell clonality analysis detected clonal T-cell receptor beta (V-J and D-J) gene rearrangements consistent with SPTCL. Her orbital and cutaneous lesions responded well to six cycles of CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) and the patient returned to functional baseline. Conclusion This case demonstrates the diagnostic difficulties when managing a patient with relapsing remitting panniculitis. Whilst the initial presentation of SPTCL here was classical, with widespread multifocal subcutaneous nodules, the appearance of facial symptoms in SPTCL is rare. Diagnostic uncertainty is frequent in both LEP and SPTCL due to the initial non-specific cutaneous presentation. This case emphasises the importance of clinicopathological correlation for accurate diagnosis. Interestingly, up to 20% of SPTCL patients have concomitant autoimmune diseases, and there is evidence suggesting a potential association between LEP and subcutaneous SPTCL beyond chance, leading some researchers to propose that these two entities exist along a spectrum. Disclosure D. Li: None. L. Spencer: None.

E012 Burden and risk factors for cardiovascular involvement in connective tissue disease

Abstract Background/Aims Connective tissue diseases (CTD) are associated with several cardiovascular manifestations. Cardiovascular diseases (CVD) are significant cause of morbidity and premature death. The pathogenesis of CVD in CTD patients is incompletely understood and likely multifactorial. Traditional risk factors for atherosclerosis are common among patients with CTD as well as metabolic syndrome. Furthermore, diabetes, dyslipidaemia, hypertension, and obesity may all be exacerbated by connective tissue disease itself or treatment with glucocorticoids. The aim of this study was to assess the burden of CVD and the risk factors for the development of cardiovascular disease in patients with CTD. Methods This was a retrospective study from a single centre. We reviewed clinical records of CTD patients as determined by treating rheumatologist. This CTD cohort included patients with systemic lupus erythematosus (SLE), myositis, systemic sclerosis, Sjogren’s syndrome, mixed and undifferentiated connective tissue diseases. Data on demographic, clinical, laboratory parameters, cardiac investigations, treatment and outcome were collected from electronic patient records. CVD and traditional risk factors were defined using standard criteria. Results A total of 298 patients with CTD were included in the analysis. Mean age of the cohort was 61±17.7 years and majority were females (n = 240, 80.5%). Of the 298 patients, 64 had CVD (21.5%). Most common CVD was ischaemic heart disease (17 patients) followed by hypertension (12), arrhythmia (9), pulmonary arterial hypertension (7), valvular diseases (5), pericardial disease (3), cardiomyopathy (3), myocarditis (2), thromboembolism (3), aortic dissection (2) and coronary spasm (1). Patient with CTD who had CVD were older (72.5±12.2 years) compared to CTD patients who did not develop CVD (non-CVD group, 57.7±17.6 years). The duration of CTD was shorter in patients with CVD (88.9±41.7 months), compared to 106±84.3 months in non-CVD group. The risk factors such as smoking, diabetes and dyslipidaemia was higher in the CVD group. Comparing CVD vs non-CVD patients respectively, systolic BP (147.1±23.0 vs 133.6±18.3mmHg), diastolic BP (83.2 ± 16.3 vs 78.2 ± 11.2mmHg) and serum uric acid (321.8±97.4 vs 292±83.9mg/dL) values were higher and statistically significant (p &amp;lt; 0.05) in CVD group. Patients with CVD had longer exposure to steroids (50%) compared to non-CVD patients (31.6%). They required high dose steroids (9.4% vs 5.6% in non-CVD patients). Current and previous DMARD use was also higher in patients who had CVD (51.6% vs 44.9%). Conclusion This study has demonstrated high burden of cardiovascular disease in CTD patients. Traditional risk factors were more prevalent in the CVD group. DMARD’s and steroid use was also higher in the CVD group. Screening for cardiovascular diseases and disease control in CTD patients is paramount for better outcomes. Further analysis will be carried out for risk factors and relevant outcomes. Disclosure K.K. Garg: None. S. Sampath: None. A. Erinjogunola: None. B. Ting: None. H. Noori: None. G.M. Koduri: None.

Fractional exhaled nitric oxide in idiopathic pulmonary arterial hypertension and mixed connective tissue disease complicating pulmonary hypertension

BackgroundFractional exhaled nitric oxide (FeNO) has been extensively studied in various causes of pulmonary hypertension (PH), but its utility as a noninvasive marker remains highly debated. The objective of our study was to assess FeNO levels in patients with idiopathic pulmonary arterial hypertension (IPAH) and mixed connective tissue disease complicating pulmonary hypertension (MCTD-PH), and to correlate them with respiratory functional data, disease severity, and cardiopulmonary function.MethodsWe collected data from 54 patients diagnosed with IPAH and 78 patients diagnosed with MCTD-PH at the Shanghai Pulmonary Hospital Affiliated to Tongji University. Our data collection included measurements of brain natriuretic peptide (pro-BNP), cardiopulmonary exercise test (CPET), pulmonary function test (PFT), impulse oscillometry (IOS), and FeNO levels. Additionally, we assessed World Health Organization functional class (WHO-FC) of each patient.Results(1) The fractional exhaled concentration of nitric oxide was notably higher in patients with IPAH compared to those with MCTD-PH. Furthermore, within the IPAH group, FeNO levels were found to be lower in cases of severe IPAH compared to mild IPAH (P = 0.024); (2) In severe pulmonary hypertension as per the WHO-FC classification, FeNO levels in IPAH exhibited negative correlations with FEV1/FVC (Forced Expiratory Velocity at one second /Forced Vital Capacity), MEF50% (Maximum Expiratory Flow at 50%), MEF25%, and MMEF75/25% (Maximum Mid-expiratory Flow between 75% and 25%), while in severe MCTD-PH, FeNO levels were negatively correlated with R20% (Resistance at 20 Hz); (3) ROC (Receiving operator characteristic curve) analysis indicated that the optimal cutoff value of FeNO for diagnosing severe IPAH was 23ppb; (4) While FeNO levels tend to be negatively correlated with peakPETO2(peak end-tidal partial pressure for oxygen) in severe IPAH, in mild IPAH they had a positive correlation to peakO2/Heart rate (HR). An interesting find was observed in cases of severe MCTD-PH, where FeNO levels were negatively correlated with HR and respiratory exchange ratio (RER), while positively correlated with O2/HR throughout the cardiopulmonary exercise test.ConclusionFeNO levels serve as a non-invasive measure of IPAH severity. Although FeNO levels may not assess the severity of MCTD-PH, their significant makes them a valuable tool when assessing severe MCTD-PH.

Antinuclear antibody (ANA) positivity pattern by line immunoassay in a hospital from eastern India: Update from a laboratory perspective

ABSTRACT Context: The existence of more than one antibody in systemic autoimmune rheumatic diseases (SARDs) or connective tissue disease (CTD) along with features of more than one autoimmune disease (AD) in an individual is suggestive of overlap syndrome (OS). Line immunoassay (LIA) can target many autoantibodies in a single approach, thus making the identification of OS feasible. Aims and Objectives: This study aimed to identify the pattern of distribution of antinuclear antibodies by LIA prevalent in a hospital population in eastern India and identify common forms of SARD in this belt based on laboratory findings. Material and Methods: A total of 1660 samples received for ANA profile testing by LIA were analysed. Statistical Analysis: Factor analysis was performed with factor loading scores used in the k-means algorithm to identify clustering of various autoantibodies. Results: U1-snRNP positivity was the highest at 16.69%, and the least frequent autoantibody noted was anti-Jo-1 at 0.71% positivity. Based on the outcome of factor analysis, three clusters were determined. Cluster 1 showed a predominance of anti-PM/Scl antibodies, cluster 2 showed a predominance of anti-dsDNA, anti-histone, anti-SmD1, anti-nucleosomes, anti-PCNA, anti-Po, anti-SSA/Ro52, anti-SSA-Ro60, anti-SSB/La, anti-Scl-70, anti-Mi-2, anti-Ku and anti-AMA-M2, and cluster 3 showed a predominance of anti-U1-snRNP. Conclusions: Mixed connective tissue disease (MCTD) and overlap syndrome (OS) are prevalent more than pure form of an AD in our study population. OS may be missed out by monospecific immunoassays and hence adds to diagnostic challenges. LIA may be more useful in identifying specific autoantibodies by a single approach rather than monospecific immunoassays in populations after a positive screen by indirect immunofluorescence (IIF).

Clinical observation of a patient with mixed connective tissue disease in an outpatient practice

Systemic connective tissue diseases are a heterogeneous group of diseases with unclear etiology, the pathogenesis of which is represented by an autoimmune process, a heterogeneous clinical picture and a variable course. Classical variants of the disease that do not cause difficulties in their verification are most common in clinical practice. But some patients have signs characteristic of various connective tissue diseases. This combination of symptoms is called mixed connective tissue disease or “cross syndrome” (Overlap-syndrome). The multi-organ nature of the clinical picture of the disease presents a diagnostic difficulty for the clinician and leads to late diagnosis, ineffective therapy, and disability of the patient. The article presents a clinical case of mixed connective tissue disease in a middle-aged patient. An analysis of literary sources, clinical data, and laboratory results was carried out.

Naifold capillaroscopy in mixed connective tissue disease patients.

Mixed connective tissue disease (MCTD) is a rare systemic disease characterized by overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermato-/polymyositis (DM/PM), and rheumatoid arthritis (RA). Naifold capillaroscopy (NFC) is a non-invasive test for evaluating the capillaries of the nail shaft used in the diagnosis of rheumatic diseases. To determine whether there are characteristic abnormalities in NFC in MCTD patients, and whether the type of NFC lesions correlates with organ involvement in these patients. Clinical picture and NFC patterns were analyzed in 43 patients with MCTD. Capillaroscopic images were divided into scleroderma-like pattern (SD-like pattern) according to the Cutolo classification, non-specific lesions, and normal images. Relationships between the clinical aspects considered in the MCTD classification criteria and the changes in the capillaroscopic images were evaluated. SD-like pattern was present in 20 MCTD patients (46.51%) with a predominance of the "early" pattern. Giant, branched, dilated capillaries and reduced capillary density were found more frequently in MCTD patients compared to the control group (p-values 0.0005, 0.005, 0.02, < 0.0001 respectively). There were associations found between the presence of a reduced number of vessels, avascular areas, and SD-like pattern with the presence of sclerodactyly in MCTD patients (p = 0.002, p = 0.006, p = 0.02, respectively), alongside an association between the presence of branched vessels and the subpapillary plexus with pulmonary arterial hypertension (PAH) (p = 0.04 and p = 0.005, respectively). MCTD patients are significantly more likely to have abnormalities upon NFC. It is worthwhile to perform capillaroscopic examination in MCTD patients. Key Points • Scleroderma-like pattern was found in more than half of the MCTD patients. • Reduced capillary density was found to be a significant predictor of the diagnosis of MCTD. • There were relationships between the presence of reduced capillary density, avascular areas, and SD-like with the presence of sclerodactyly in the MCTD patients. • There was an association between the presence of branched vessels and the visibility of the subpapillary plexus and pulmonary arterial hypertension (PAH).

Exploring paediatric rheumatology care: a ten-year retrospective analysis of the patient population in Ghana

BackgroundRheumatic diseases can seriously impact children’s general health, development, and growth. However, due to a lack of resources, paediatric rheumatology is a largely underdeveloped speciality in many African nations. Children with rheumatic disorders face obstacles in accessing specialized medical care, including lack of specialists, care centres, medication access, and limited research and education to increase understanding of paediatric rheumatic disease among healthcare practitioners. This study described the disease characteristics, prevalence, and challenges faced by paediatric rheumatic disease patients receiving care at a teaching hospital in Accra, Ghana.MethodsA retrospective record-based study was conducted among all paediatric cases presenting to the rheumatology clinic of the Korle Bu Teaching Hospital (KBTH) from January 2011 to December 2021. Data collected include clinical features, laboratory findings at disease presentation, andtherapeutic regimens prescribed per standard guidelines and experiences.ResultsA total of 121 cases were identified as of 2021, indicating a point prevalence of 0.0011%. The majority (73%) were females with a mean age of 13.4 ± 3.2 years. The mean duration of symptoms in months experienced by patients before being successfully referred to a rheumatologist was 18 months. There were significant differences between referred and confirmed diagnoses, especially in cases involving mixed connective tissue diseases (MCTD), systemic lupus erythematosus (SLE), and juvenile dermatomyositis (JDM), suggesting that these conditions may be under-recognised. Arthralgia and arthritis were the most common presenting symptoms. More than three-quarters (86.8%) of the cases studied were treated with steroids (oral or intravenous). In cases requiring immunosuppressive therapy, methotrexate was the most commonly prescribed in 33.9% of instances. Mortality was recorded at 8.3%, with the majority involving SLE cases. Most (95.7%) of the primary caregivers expressed positive experiences regarding care received at the adult rheumatology clinic.ConclusionThere were significant delays in diagnosis and diagnostic accuracy for patients with paediatric rheumatic disease (PRD). This highlights the pressing need for strengthening paediatric rheumatology services in Africa, including increasing awareness about these conditions among the public and healthcare providers to improve early diagnosis and quality of life for children with these conditions.

Pulmonary Hypertension in Connective Tissue Diseases Other than Systemic Sclerosis.

Pulmonary hypertension (PH) is a known complication of certain connective tissue diseases (CTDs), with systemic sclerosis (SSc) being the most common in the Western world. However, PH in association with non-SSc CTD such as systemic lupus erythematous, mixed connective tissue disease, and primary Sjögren's syndrome constitutes a distinct subset of patients with inherently different epidemiologic profiles, pathophysiologic mechanisms, clinical features, therapeutic options, and prognostic implications. The purpose of this review is to inform a practical approach for clinicians evaluating patients with non-SSc CTD-associated PH.The development of PH in these patients involves a complex interplay between genetic factors, immune-mediated mechanisms, and endothelial cell dysfunction. Furthermore, the broad spectrum of CTD manifestations can contribute to the development of PH through various pathophysiologic mechanisms, including intrinsic pulmonary arteriolar vasculopathy (pulmonary arterial hypertension, Group 1 PH), left-heart disease (Group 2), chronic lung disease (Group 3), chronic pulmonary artery obstruction (Group 4), and unclear and/or multifactorial mechanisms (Group 5). The importance of diagnosing PH early in symptomatic patients with non-SSc CTD is highlighted, with a review of the relevant biomarkers, imaging, and diagnostic procedures required to establish a diagnosis.Therapeutic strategies for non-SSc PH associated with CTD are explored with an in-depth review of the medical, interventional, and surgical options available to these patients, emphasizing the CTD-specific considerations that guide treatment and aid in prognosis. By identifying gaps in the current literature, we offer insights into future research priorities that may prove valuable for patients with PH associated with non-SSc CTD.

The utility of layering systemic therapies in connective tissue diseases

AbstractBackgroundCutaneous manifestations in connective tissue diseases (CTDs) are often chronic and difficult to control.ObjectivesThis study aims to review the use of combination systemic medications in CTDs and assess disease response.MethodsAn IRB‐approved, retrospective chart review was conducted at a single large academic institution in New Orleans, Louisiana. Inclusion criteria were adult patients with CTDs on two or more systemic therapies.ResultsOut of 101 patients, 37.62% were taking combination systemic agents. Of these patients, 44% were diagnosed with lupus, 18% with dermatomyositis (DM), 8% with systemic scleroderma (SSc), 10% with morphea/limited scleroderma (M), 12% with mixed connective tissue disease (MCTD), and 8% with rheumatoid arthritis (RA). The most common regimen for lupus, MCTD, and SSc patients was hydroxychloroquine (HCQ) + prednisone (PRED) + mycophenolate mofetil (MMF). DM patients were most commonly taking combinations of the above regimen with intravenous immunoglobulin (IVIG). Morphea and RA patients were on multiple combinations of steroid and nonsteroidal agents including MMF, IVIG, azathioprine, methotrexate, HCQ, sulfasalazine, upadacitinib, apremilast, and tofacitinib.ConclusionsThis study aims to assess the efficacy of combination systemic medications and disease response in CTDs. Lupus was the most common CTD in our study, with patients taking 2–4 combination medications. HCQ, MMF, and PRED were the most common medications used within a combination regimen with minimal adverse effects. Though our study has several limitations including its retrospective nature and small sample size, it shows that CTDs can be resistant to monotherapy and that combination therapy might be required. More research in layering systemic agents is needed since this topic is currently limited to minimal case series and clinical trials.

Renal Manifestation of Mixed Connective Tissue Disease

Abstract A young female presented with facial puffiness and swelling in both lower limbs for 3 months, distension of the abdomen, and breathlessness on exertion for 1 month with a history of hypertension and hypothyroid on regular treatment. On general physical examination, there were pallor, bilateral pitting edema, tachycardia, and blood pressure of 190/100 mmHg. Abdominal examination revealed shifting dullness. Respiratory and cardiovascular systems were normal. Fundoscopy revealed Grade 1 papilledema, and the rest of the neurological examination was unremarkable. Investigations showed normocytic normochromic anemia, serum creatinine of 1.6 mg/dl, and hypoalbuminemia; urine R/E showed significant proteinuria; and anti-U1 ribonucleoprotein particle antibodies were positive. Two-dimensional echocardiography showed mild concentric left ventricular hypertrophy and mild pericardial effusion. Ultrasonography abdomen showed bilateral renal parenchymal disease and moderate ascites. Renal biopsy revealed diffuse proliferative glomerulonephritis and lupus nephritis Class IV. Renal manifestation is very rare in mixed connective tissue disease as an initial presentation

Machine learning-driven immunophenotypic stratification of mixed connective tissue disease corroborating the clinical heterogeneity.

To stratify patients with mixed connective tissue disease (MCTD) based on their immunophenotype. We analyzed the immunophenotype and transcriptome of 24 immune cell subsets from patients with MCTD, systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM), and systemic sclerosis (SSc) from our functional genome database, ImmuNexUT (https://www.immunexut.org/). MCTD patients were stratified by employing machine learning models including Random Forest, trained by immunophenotyping data from SLE, IIM, and SSc patients. Transcriptomes were analyzed with gene set variation analysis (GSVA) and clinical features of MCTD subgroups were compared. This study included 215 patients, including 22 patients with MCTD. Machine learning models, constructed to classify SLE, IIM, and SSc patients based on immunophenotyping, were applied to MCTD patients, resulting in 16 classified as SLE-immunophenotype and 6 as non-SLE-immunophenotype. Among MCTD patients, patients with the SLE-immunophenotype had higher proportions of Th1 cells [2.85% (interquartile range (IQR) 1.54-3.91) vs 1.33% (IQR 0.99-1.74) p= 0.027] and plasmablasts [6.35% (IQR 4.17-17.49) vs 2.00% (IQR 1.20-2.80) p= 0.010]. Notably, the number of SLE-related symptoms was higher in patients with the SLE-immunophenotype [2.0 (IQR 1.0-2.0) vs 1.0 (IQR1.0-1.0) p= 0.038]. Moreover, GSVA scores of interferon-α and -γ responses were significantly higher in patients with the SLE-immunophenotype in central memory CD8+ T cells, while hedgehog signalling was higher in non-SLE-immunophenotype patients in 5 cell subsets. This study describes the stratification of MCTD patients based on immunophenotyping, suggesting the presence of distinct immunological processes behind the clinical subtypes of MCTD.

Multiple-autoimmune syndrome causing interstitial lung disease in the presence of pulmonary hypertension and Erasmus syndrome

Connective tissue diseases constitute a group of inflammatory disorders that can concurrently affect multiple organs. Pulmonary manifestations of connective tissue diseases include interstitial lung disease, pulmonary hypertension, pleural diseases, and airway compromise. Both interstitial lung disease and pulmonary arterial hypertension have high morbidity and mortality in these patients. Interstitial lung disease affects 40 % - 50 % of patients with connective tissue diseases, predominantly systemic sclerosis, rheumatoid arthritis, and inflammatory myopathies. Parenchymal compromise is heterogeneous and depends on the underlying disease. Conversely, pulmonary arterial hypertension is found mostly in systemic sclerosis, systemic lupus erythematosus and mixed connective tissue disease. Delays and the diagnosis of connective tissue disorder associated interstitial lung disease are frequent as evidence is limited and as they often present concomitantly or overlap with other pulmonary diseases. Timely diagnosis and treatment are fundamental to decrease mortality. Treatment varies by the type of connective tissue disease, nevertheless, evidence of these complications in the context of multiple-autoimmune syndrome is still limited.&#x0D; We present a complex case of a 47-year-old male with a multiple-autoimmune syndrome (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome and mixed connective tissue disease) complicated by interstitial lung disease and pulmonary hypertension, and occurring concurrently with silicosis (Erasmus syndrome), and pulmonary embolism. This case shows the diverse manifestations of connective tissue of the lungs, emphasizes the intricate nature of diagnosing and managing connective tissue disorder-related pulmonary complications in the context of multiple autoimmune syndromes, and the importance of a multidisciplinary team for the diagnostic and therapeutic approach of the patient.

Prevalence of ocular toxicity induced by antimalarial drugs in patients with rheumatic diseases

Several studies have reported the possibility of ocular toxicity with the use of antimalarial drugs by patients with rheumatic diseases. Thus, the present study intended to investigate the prevalence of such toxicity in these patients and the feasibility of the regression of changes after medication discontinuation. The present retrospective study included the medical records of 598 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disorders (MCTDs) who took chloroquine (CQ) or hydroxychloroquine (HCQ) and underwent routine ophthalmologic examinations. Moreover, if a patient had any ocular abnormality reported by the examining ophthalmologist, he/she was referred to another ophthalmologist to confirm the primary findings. Also, the patients with abnormal ocular findings who discontinued the drugs were re-examined 12 months after the drug discontinuation to evaluate the rate of regression of the ocular changes. According to our findings, 81 out of 598 patients (13.6%) had ocular toxicity in routine ophthalmologic examinations. However, ocular changes were ruled out in 49 (8.2%) patients using a second examination by another ophthalmologist. Therefore, retinopathy was confirmed in 32 out of 598 (5.4%) cases. Moreover, the patients with eye complications were significantly older than those without ocular toxicity (P = 0.03), while no significant relationship was found between ocular toxicity and other variables. Finally, of 32 patients with ocular toxicity, 12 patients were re-examined 12 months after the drug discontinuation, revealing normal findings in 7 (58%) patients, while 5 (42%) had irreversible ocular abnormalities. According to our findings, the prevalence of HCQ- and CQ-induced retinopathy was quite considerable in patients receiving these drugs. Therefore, despite the current controversies, we recommend that all patients receiving antimalarial drugs undergo screening for ocular toxicity.

Macitentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease (CTD-PAH): Real-World Evidence from the Combined OPUS/OrPHeUS Dataset.

Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. gov Graphical abstract available for this article.

Pulmonary Manifestations of Systemic Lupus Erythematosus Among Adults in Aseer Region, Saudi Arabia.

Nearly half of the Systemic lupus erythematosus (SLE) patients develop lung involvement. The study assessed the extent of pulmonary involvement among SLE patients and to identify the associated factors in the population. This retrospective cohort study was conducted at Aseer Hospital and Khamis Myshat Hospital in the Southern region of Saudi Arabia. The study spanned from January 1, 2016, to June 3, 2023. Patient inclusion criteria encompassed individuals who received a definitive diagnosis and classification as per American College of Rheumatology criteria, while patients under 18 years of age and those with mixed connective tissue diseases were exclude. A total of 247 participants were included. 41.7% (n=103) aged 41 years and older, 95.1% (n = 235) were females. Around 10.10% had diabetes mellitus and 17.00% had hypertension and hypothyroidism. Lupus Nephritis was in 15.40%. Chest involvement was reported in 21.9%, in the form of pleuritis (6.10%), pleural effusion (4.00%), and lupus pneumonitis (4.00%), interstitial lung disease (4.00%), pulmonary embolism (3.60%) of individuals, and pulmonary hemorrhage (2.80%). The respiratory symptoms reported by SLE were; dyspnea, cough, and chest pain each having a prevalence of around 18.0%. Palpitations have a relatively high occurrence at 13.80%. Meanwhile, hemoptysis (blood coughing) has a lower prevalence of 1.20%, and fever is reported at 2.80%. Having chronic kidney disease and hypertension were significantly associated with having pulmonary involvement; (χ2=3.308, p=0.027) and (χ2=7.782, Fisher's p=0.002) respectively. The seropositivity for antiphospholipid Abs, anti-CCP, and antids-DNA were significantly associated with pulmonary involvement (χ2=3.239, =p=0.049), (χ2=4.621, Fisher's p=0.023), and (χ2=8.248, p=0.010) respectively. The study found that 21.9% of SLE patients experience chest involvement, with varying degrees of pulmonary symptoms. Factors such as chronic kidney disease, hypertension, antiphospholipid antibodies, Anti-CCP positivity, and seropositivity for Anti-dsDNA were found to be significant associations with lung involvement, contributing to our understanding of SLE.

Mixed connective tissue disease with juvenile onset: results of a retrospective single-center study

Mixed connective tissue disease (MCTD) is one of the very rare systemic autoimmune diseases; it accounts for 0.1–0.6% of cases in pediatric rheumatologists' practices. MCTD is characterized by a broad spectrum of clinical manifestations and a high frequency of extremely unspecific symptoms at the onset, with the overall picture of the disease forming slowly and gradually. The diagnosis is often delayed and confirmed only at an advanced stage of organ dysfunction with the development of irreversible changes.Objective: to identify a group of patients fulfilling the criteria for MCTD in an open, single-center, continuous retrospective study among anti-ribonucleoprotein (anti-RNP) antibody-positive patients and to analyze their demographic, clinical and laboratory characteristics and therapy.Material and methods. All anti-RNP-positive patients admitted to the pediatric department of V.A. Nasonova Research Institute of Rheumatology from 2019 to 2023 and meeting at least one of the variants of the MCTD criteria (Kasukawa, Alarcуn-Segovia, Kahn and Sharp criteria) were included in the study.Results and discussion. 18 (56.25%, 17 girls and 1 boy) of 32 anti-RNP-positive patients fulfilled criteria for MCTD. Patients most frequently fulfilled a combination of criteria – Sharp and Kahn (n=8) or Alarcуn-Segovia and Kahn (n=8). The median age of onset of MCTD was 12.2 [9.7; 13.9] years. The most common clinical manifestations were arthritis (100%), various skin lesions (94.4 %), Raynaud's phenomenon (88.9%), lymphadenopathy (72.2%) and general constitutional disorders (50%). Sjögren's syndrome (SS) was diagnosed in 17 (94.4%) patients. All patients had antinuclear factor (ANF) 1/1280, and the anti-RNP level was &gt;200 U/ml. There were also antibodies against double-stranded DNA (n=5), Ro- (n=4) and Sm- (n=5) antigens. An IgM rheumatoid factor was detected in 6 patients and hypergammaglobulinemia in 10 patients. Capillaroscopic changes in the nailfold with predominant scleroderma type were found in 77.8% of patients. The most common combination was of Raynaud's phenomenon, arthritis, SS, lymphadenopathy and hypergammaglobulinemia (50%). All patients received glucocorticoids, 9 – hydroxychloroquine, 8 – methotrexate, 3 – mycophenolate mofetil, 1 – cyclophosphamide, 1 – azathioprine. Biologic DMARDs (bDMARDs) were prescribed to 12 (66.7%) patients: 3 – rituximab, 8 – abatacept, 1 – belimumab, with an acceptable safety profile and initial efficacy.Conclusion. Most patients in the study met the Kahn criteria. Only 2 patients met all variants of the criteria, which indicates the need to use a combination of criteria when a MCTD is suspected. A combination of Raynaud's phenomenon, arthritis, SS, lymphadenopathy and hypergammaglobulinemia was observed in half of patients with MCTD. The presence of Raynaud's phenomenon and high ANF titer in children with rheumatic diseases, especially with a polymorphic clinical picture, requires the inclusion of MCTD in differential diagnosis. Preliminary results indicate the safety of the use of biologic drugs in children with MCTD.